The skin, as the largest organ of the body, has long been considered as promising route for the administration of therapeutic agents. Since the skin is an excellent natural barrier against foreign substances, it is highly impermeable to therapeutic agents. In order to enhance skin permeability, scientists have tried many different penetration enhancement technologies, including adding chemical enhancer, sonophoresis, iontophoresis, and microneedle. Compare to aforementioned technologies, nano-vesicular delivery system obtains plenty of attentions due to various advantages, such as minimization of drug degradation and drug loss, increase of drug bioavailability and drug accumulation in the target area, prevention of harmful toxic effects, versatility and flexibility in handling drug with better patient compliance.
Nano-vesicular delivery system can broadly be classified into lipid based carriers and polymeric based colloidal carriers according to the basis of the main formulation component. These two families share the same advantages, such as controlled particle size, enhanced skin penetration and controlled release. The key difference between lipid and polymer based carriers is that the former are mainly composed of physiological lipids and hence they are more biocompatible, and can be degraded to non-toxic residues without safety issues caused by polymeric materials. Various lipid nano-carriers for skin care have been disclosed, such as liposome, ethosome, microemulsion, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and solid-in-oil nano-dispersion. As such three types of lipid nano-vesicles, including microemulsion, NLC and solid-in-oil nanodispersions, are presented as examples in this invention to enhance skin penetration of either hydrophobic or hydrophilic active ingredients. These examples are given only for a better understanding of the present proposal, and not intended to limit the scope of the proposal in any way.
Microemulsions or nanoemulsions are thermodynamically stable isotropic dispersions, transparent, with low viscosity, consisting of oil and water stabilized by an interfacial film of surfactant molecules, typically in conjunction with a co-surfactant. The skin penetration-enhancing efficacy of the nanoemulsions can be attributed to the combined effect of both the lipophilic and the hydrophilic domains of the microemulsions. The lipid domain can directly partition into lipids of stratum corneum, or lipid vesicles themselves can intercalate between the lipid chains of the stratum corneum, thereby destabilizing its bilayer structure, leading to a pathway for drug penetration. On the other hand, the hydrophilic domain of the nanoemulsion can hydrate the stratum corneum to a greater extent leading to an increased passive percutaneous drug flux. As some lipid chains are covalently attached to the corneocytes, hydration of these proteins will also lead to the disorder of the lipid bilayers which further enhances the drug transport. Many studies have illustrated that microemulsion formulations possessed improved transdermal and dermal delivery properties for different drugs, such as estradiol, meloxicam, methotrexate and clindamycin phosphate. In order to achieve a better skin penetration of active ingredients, transdermal penetration enhancer incorporated nanoemulsion has been developed. V. Prasad Shastri' s group demonstrated a novel microemulsion system with oleyl alcohol and n-methyl pyrrolidone (NMP) as penetration enhancers to deliver two hydrophilic drugs (diltiazem HCl and lidocaine HCl) and two hydrophobic drugs (estradiol and lidocaine free base). A comparison between oil-in-water (o/w) with water-in-oil (w/o) nanoemulsion indicated that the former provides higher enhancement for both hydrophilic and hydrophobic drugs. The enhancement of drug permeability from the o/w microemulsion system is 17-fold for lidocaine free base, 30-fold for lidocaine HCl, 58-fold for estradiol, and 520-fold for diltiazem HCl when compared to aqueous solution.
Nanostructured lipid carriers (NLC) is derived from emulsions by simply replacing some the liquid lipid (oil) by a solid lipid, i.e. being solid at body temperature. There are five major advantages of NLC compared to other conventional carriers: (1) low toxicity and excellent tolerability due to the presence of physiological and biodegradable lipids; (2) small particle size which ensures a closer contact to the stratum corneum and increased skin penetration of drugs; (3) controlled release for many substances due to the solid matrix; (4) increased skin hydration effect due to the occlusive properties of lipid nanoparticles and (5) enhanced chemical stability of compounds which are sensitive to light, oxidation and hydrolysis. Due to the hydrophobic matrix, solid lipids particles have been widely used in deliver poor water soluble drugs to enhance their skin penetration and also the stability.
Solid-in-oil nanodispersion is another emulsion based delivery system. Typically, it is prepared by creating a water-in-oil emulsion followed by solvent and water removal. The resulted nanoparticles are dispersed in oil to form solid-in-oil nanodispersion which is comprised of active ingredient, surfactant and oil. Solid-in-oil nanodispersion has long been used in transdermal delivery for active ingredients, especially the hydrophilic proteins. Masahiro Goto's group has demonstrated that the skin penetration of insulin of 6 kDa, enhanced green fluorescent protein (EGFP) of 27 kDa and horseradish peroxidase (HRP) of 40 kDa could be enhanced in soild-in-oil nanodispersion compared to that of control. The same group also demonstrated that permeation efficiency through skin of an anti-rheumatic agent called methotrexate in solid-in-oil nanodispersion has a two- to three-fold increase compared to that of the control aqueous solution. Addition of urea as enhancer in the aforementioned dispersion achieves approximately 8.8-fold increase compared to that of the control aqueous solution after 24 h.
However, the abovementioned conventional technologies, especially lipid vesicle, have the disadvantages that their processing steps are complicated and they involve organic solvent which is harmful to human skin.